Thiazoles, imidazoles, and pyrazoles useful as inhibitors of protein kinases

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds, to methods of using the compounds and to the compositions in the treatment of various disease, conditions, or disorders. The invention also relates to processes for preparing compounds of the inventions.

CROSS REFERENCE TO RELATED APPLICATIONS

This present application is a divisional application of U.S. patentapplication Ser. No. 11/786,464, filed on Apr. 11, 2007, which in turnclaims the benefit, under 35 U.S.C. §119, to U.S. ProvisionalApplication No. 60/791,083, filed Apr. 11, 2006. The entire teachings ofthe above-mentioned applications are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also relates to pharmaceuticallyacceptable compositions comprising the compounds of the invention andmethods of using the compositions in the treatment of various disorders.The invention also relates to processes for preparing the compounds ofthe invention.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego,Calif.: 1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596;Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992,70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor a (TNF-a)), and growth factors (e.g.,granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, autoimmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

One kinase family of particular interest is the Src family of kinases.These kinases are implicated in cancer, immune system dysfunction andbone remodeling diseases. For general reviews, see Thomas and Brugge,Annu. Rev. Cell Dev. Biol. 1997, 13, 513; Lawrence and Niu, Pharmacol.Ther. 1998, 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) 2000,65, 49-58; Boschelli et al., Drugs of the Future 2000, 25(7), 717.

Members of the Src family include the following eight kinases inmammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and Blk. These arenonreceptor protein kinases that range in molecular mass from 52 to 62kD. All are characterized by a common structural organization that iscomprised of six distinct functional domains: Src homology domain 4(SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain(SH1), and a C-terminal regulatory region. Tatosyan et al. Biochemistry(Moscow) 2000, 65, 49-58.

Based on published studies, Src kinases are considered as potentialtherapeutic targets for various human diseases. Mice that are deficientin Src develop osteopetrosis, or bone build-up, because of depressedbone resorption by osteoclasts. This suggests that osteoporosisresulting from abnormally high bone resorption can be treated byinhibiting Src. Soriano et al., Cell 1992, 69, 551 and Soriano et al.,Cell 1991, 64, 693.

Suppression of arthritic bone destruction has been achieved by theoverexpression of CSK in rheumatoid synoviocytes and osteoclasts.Takayanagi et al., J. Clin. Invest. 1999, 104, 137. CSK, or C-terminalSrc kinase, phosphorylates and thereby inhibits Src catalytic activity.

This implies that Src inhibition may prevent joint destruction that ischaracteristic in patients suffering from rheumatoid arthritis.Boschelli et al., Drugs of the Future 2000, 25(7), 717.

Src also plays a role in the replication of hepatitis B virus. Thevirally encoded transcription factor HBx activates Src in a steprequired for propagation of the virus. Klein et al., EMBO J. 1999, 18,5019, and Klein et al., Mol. Cell. Biol. 1997, 17, 6427.

A number of studies have linked Src expression to cancers such as colon,breast, hepatic and pancreatic cancer, certain B-cell leukemias andlymphomas. Talamonti et al., J. Clin. Invest. 1993, 91, 53; Lutz et al.,Biochem. Biophys. Res. 1998 243, 503; Rosen et al., J. Biol. Chem. 1986,261, 13754; Bolen et al., Proc. Natl. Acad. Sci. USA 1987, 84, 2251;Masaki et al., Hepatology 1998, 27, 1257; Biscardi et al., Adv. CancerRes. 1999, 76, 61; Lynch et al., Leukemia 1993, 7, 1416. Furthermore,antisense Src expressed in ovarian and colon tumor cells has been shownto inhibit tumor growth. Wiener et al., Clin. Cancer Res., 1999, 5,2164; Staley et al., Cell Growth Diff. 1997, 8, 269.

Other Src family kinases are also potential therapeutic targets. Lckplays a role in T-cell signaling. Mice that lack the Lck gene have apoor ability to develop thymocytes. T-cells lacking Lck are shown to beseverely impaired in TCR tyrosine phosphorylation and subsequentactivation via the TCR. Straus et al., Cell 1992, 70, 585; Chan et al.,Ann. Rev. Immunol. 1994, 12, 555; Weiss et al., Cell 1994, 76, 263;Hanke et al., J. Biol. Chem. 1996, 271, 695; Van Oers at al., Immunity1996, 5, 429. The function of Lck as a positive activator of T-cellsignaling suggests that Lck inhibitors may be useful for treating of Tcell mediated disorders such as autoimmune and inflammatory diseases andin the prevention of solid organ transplant rejection. Molina et al.,Nature, 1992, 357, 161; Hanke et al., Inflammation Res. 1995, 44, 357.Hck, Fgr and Lyn have been identified as important mediators of integrinsignaling in myeloid leukocytes. Lowell et al., J. Leukoc. Biol., 1999,65, 313. Inhibition of these kinase mediators may therefore be usefulfor treating inflammation. Boschelli et al., Drugs of the Future 2000,25(7), 717.

SUMMARY OF THE INVENTION

Compounds of this invention, and pharmaceutically acceptablecompositions thereof, are useful as inhibitors of protein kinases. Insome embodiments, these compounds are effective as inhibitors of Srcfamily protein kinases; in some embodiments, as inhibitors of Lckprotein kinases. These compounds have the formula I, as defined herein,or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions thereof areuseful for treating or preventing a variety of diseases, disorders orconditions, including, but not limited to, an autoimmune, inflammatory,proliferative, or hyperproliferative disease, animmunologically-mediated disease, or bone disease. The compoundsprovided by this invention are also useful for the study of kinases inbiological and pathological phenomena; the study of intracellular signaltransduction pathways mediated by such kinases; and the comparativeevaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof;wherein

-   R¹ is a 3-7 membered monocyclic cycloalkyl optionally substituted    with 0-4 J¹;-   Ring

-   R⁴ is H, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, halo(C₁₋₄ aliphatic),    3-8 membered heterocyclyl, halo, NO₂, CN, OH, OR″, SH, SR″, NH₂,    N(H)R″, N(R″)₂, COH, COR″, CO₂H, CO₂R″, C(O)NH₂, C(O)NHR″, C(O)NR″₂,    OC(O)R″, OC(O)NH₂, OC(O)NHR″, OC(O)N(R″)₂, N(H)C(O)R″, N(R″)C(O)R″,    N(H)CO₂R″, N(R″)CO₂R″, N(H)CO₂H, N(R″)CO₂H, N(H)CONH₂,    N(H)C(O)N(H)R″, N(H)C(O)N(R″)₂, SO₂NH₂, SO₂N(H)R″, SO₂N(R″)₂,    N(H)SO₂R″, N(R″)SO₂R″, P(O)R′, P(O₂)R′, P(O)R′₂, or P(O)OR′²;-   R″ is unsubstituted C₁₋₆aliphatic or C₁₋₄ haloaliphatic; or two R″    groups, together with the atom to which they are bound, form an    unsubstituted 3-8 membered nonaromatic monocyclic ring having 0-1    heteroatoms independently selected from O, N, and S;

T¹ is a C₁₋₆ aliphatic chain wherein 0-3 methylene units of the chainare optionally replaced with —NR—, —O—, —S—, —C(O)—, —C(═NR)—,—C(═NOR)—, —SO—, or —SO₂—; each T¹ is optionally substituted with 0-2J^(T);

-   R⁵ is a 5-10 membered aromatic ring containing 0-4 heteroatoms    selected from O, N, and S; each R⁵ is optionally substituted with    0-5 J⁵;-   J⁵ is H, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, halo(C₁₋₄ aliphatic),    3-8 membered heterocyclyl, halo, NO₂, CN, OH, OR′, SH, SR′, NH₂,    NHR′, N(R′)₂, C(O)H, C(O)R′, CO₂H, CO₂R′, C(O)NH₂, C(O)N(H)R′,    C(O)NR′₂, OC(O)R′, OC(O)NH₂, OC(O)N(H)R′, OC(O)NR′₂, N(H)C(O)R′,    N(R′)C(O)R′, N(H)CO₂R′, N(R′)CO₂R′, N(H)CO₂H, N(R′)CO₂H, N(H)CONH₂,    N(H)C(O)N(H)R′, N(H)C(O)NR′₂, SO₂NH₂, SO₂N(H)R′, SO₂NR′₂, N(H)SO₂R′,    N(R′)SO₂R′, P(O)R′, PO₂R′, P(O)R′₂, or P(O)(OR′)₂;-   R is H or unsubstituted C₁₋₆aliphatic;

R′ is unsubstituted C₁₋₆aliphatic or C₁₋₄ haloaliphatic; or two R′groups, together with the atom to which they are bound, form anunsubstituted 3-8 membered nonaromatic monocyclic ring having 0-1heteroatoms independently selected from O, N, and S;

-   J¹ is M¹ or -Y¹-M¹;-   each Y¹ is independently an unsubstituted C₁₋₆aliphatic optionally    replaced with 0-3 occurrences of —NR—, —O—, —S—, —C(O)—, —SO—, or    —SO₂—;-   each M¹ is independently H, C₁₋₆ aliphatic, C₃₋₈cycloaliphatic,    halo(C₁₋₄ aliphatic), —O(haloC₁₋₄ aliphatic), 3-8 membered    heterocyclyl, 5-6 membered heteroaryl, phenyl, halo, NO₂, CN, OH,    OR′, SH, SR′, NH₂, N(H(R′, N(R′)₂, C(O)H, C(O)R′, CO₂H, CO₂R′,    C(O)NH₂, C(O)N(H)R′, C(O)NR′₂, OC(O)R′, OC(O)NH₂, OC(O)N(H(R′,    OC(O)NR′₂, N(H)C(O)R′, N(R′)C(O)R′, N(H)CO₂R′, N(R′)CO₂R′, N(H)CO₂H,    N(R′)CO₂H, N(H)C(O)NH₂, N(H)C(O)N(H)R′, N(H)C(O)NR′₂, SO₂NH₂,    SO₂NHR′, SO₂N(R′)₂, NHSO₂R′, NR′SO₂R′, P(O)R′, PO₂R′, P(O)R′₂, or    P(O) (OR′)₂;-   each R⁴, J⁵, and M¹ is independently and optionally substituted with    0-5 J;-   each J^(T) and J is independently H, halo, C₁₋₆ aliphatic,    C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄    aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —C(O)(C₁₋₄ aliphatic),    C(O)NH₂, C(O)N(H)(C₁₋₄ aliphatic), C(O)N(C₁₋₄ aliphatic)₂, —CO₂H,    —CO₂(C₁₋₄ aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄    aliphatic);-   p is 0-4.

These compounds, and pharmaceutically acceptable compositions thereof,are useful for treating or lessening the severity of a variety ofdisorders including hypercalcemia, osteoporosis, osteoarthritis, cancer,symptomatic treatment of bone metastasis, Paget's disease, autoimmunediseases such as transplant rejection, allergies, rheumatoid arthritis,and leukemia.

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, a specified number range of atoms includes anyinteger therein. For example, a group having from 1-4 atoms could have1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, recovery, purification, and use for one or moreof the purposes disclosed herein. In some embodiments, a stable compoundor chemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation that has a single point ofattachment to the rest of the molecule. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, or alkynyl groups. Specific examples include, but are notlimited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl,n-butenyl, ethynyl, and tert-butyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or“cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon or bicyclicC₈-C₁₂ hydrocarbon that is completely saturated or that contains one ormore units of unsaturation, but which is not aromatic, that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. Suitablecycloaliphatic groups include, but are not limited to, cycloalkyl andcycloalkenyl groups. Specific examples include, but are not limited to,cyclohexyl, cyclopropenyl, and cyclobutyl.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic, or tricyclic ring systems inwhich one or more ring members are an independently selected heteroatom.In some embodiments, the “heterocycle”, “heterocyclyl”, or“heterocyclic” group has three to fourteen ring members in which one ormore ring members is a heteroatom independently selected from oxygen,sulfur, nitrogen, or phosphorus, and each ring in the system contains 3to 7 ring members.

Suitable heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached through an oxygen (“alkoxy”) orsulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. The terms “halogen”, “halo”, and “hal” mean F,Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”. Suitable heteroaryl rings include, but arenot limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired functional groups in a compound with multiple reactivesites. In certain embodiments, a protecting group has one or more, orpreferably all, of the following characteristics: a) is addedselectively to a functional group in good yield to give a protectedsubstrate that is b) stable to reactions occurring at one or more of theother reactive sites; and c) is selectively removable in good yield byreagents that do not attack the regenerated, deprotected functionalgroup. As would be understood by one skilled in the art, in some cases,the reagents do not attack other reactive groups in the compound. Inother cases, the reagents may also react with other reactive groups inthe compound. Exemplary protecting groups are detailed in Greene, T. W.,Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition,John Wiley & Sons, New York: 1999 (and other editions of the book), theentire contents of which are hereby incorporated by reference. The term“nitrogen protecting group”, as used herein, refers to an agents used totemporarily block one or more desired nitrogen reactive sites in amultifunctional compound. Preferred nitrogen protecting groups alsopossess the characteristics exemplified above, and certain exemplarynitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999, the entire contents of whichare hereby incorporated by reference.

In some embodiments, the methylene units of an alkyl or aliphatic chaincan be optionally replaced with another atom or group. Examples of suchatoms or groups would include, but are not limited to, —NR—, —O—,—C(O)—, —C(═N—CN)—, —C(═NR)—, —C(═NOR)—, —S—, —SO—, or —SO₂—. Theseatoms or groups can be combined to form larger groups. Examples of suchgroups include, but are not limited to, —OC(O)—, —C(O)CO—, —CO₂—,—C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—,—OC(O)NR—, and —NRSO₂NR—, wherein R is defined herein.

Unless otherwise specified, the optional replacements form a chemicallystable compound. Optional replacements can occur both within the chainand at either end of the chain; i.e. both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound.

The optional replacements can also completely replace all of the carbonatoms in a chain. For example, a C₃ aliphatic can be optionally replacedby —NR—, —C(O)—, and —NR— to form —NRC(O)NR— (a urea).

Unless otherwise specified, if the replacement occurs at the terminalend, the replacement atom is bound to an H on the terminal end. Forexample, if —CH₂CH₂CH₃ were optionally replaced with —O—, the resultingcompound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, geometric,conformational, and rotational forms of the structure). For example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers are included inthis invention. As would be understood to one skilled in the art, asubstituent can freely rotate around any rotatable bonds. For example, asubstituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, geometric, conformational, or rotational mixtures of thepresent compounds are within the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable salt.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds. Acid addition saltscan be prepared by 1) reacting the purified compound in its free-basedform with a suitable organic or inorganic acid and 2) isolating the saltthus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate,heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oleate, oxalate, palmitate, palmoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate,salicylate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like. Saltsderived from appropriate bases include alkali metal, alkaline earthmetal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisionsthe quaternization of any basic nitrogen-containing groups of thecompounds disclosed herein. Water or oil-soluble or dispersible productsmay be obtained by such quaternization.

Base addition salts can be prepared by 1) reacting the purified compoundin its acid form with a suitable organic or inorganic base and 2)isolating the salt thus formed. Base addition salts include alkali oralkaline earth metal salts. Representative alkali or alkaline earthmetal salts include sodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable acid or base addition salts.

The following abbreviations are used:

DMSO dimethyl sulfoxide DCM dichloromethane THF tetrahydrofuran ATPadenosine triphosphate HEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid NMR nuclear magneticresonance HPLC high performance liquid chromatography LCMS liquidchromatography-mass spectrometry Rt retention time TBABr₃tetrabutylammonium tribromide

One embodiment of this invention provides compounds of formula II:

wherein R¹, R⁴, T⁵, T¹, Ring A, and p are defined herein.

In one embodiment of this invention, R¹ is a 5 or 6 membered cycloalkylring. In another embodiment, R¹ is cyclopentyl. In yet anotherembodiment, R¹ is cyclohexyl.

In some embodiments, Ring

In other embodiments, Ring

In yet other embodiments, Ring

In some embodiments,

Ring

In some embodiments of the present invention, R⁴ is H, halo, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —CO(C₁₋₄ aliphatic),CONH₂, CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).

In some embodiments, T¹ is O, N, S, —C(O)N(R)— or —N(R)C(O)—. In otherembodiments, T¹ is O. In some embodiments, R is H.

In one embodiment of this invention, R⁵ is an optionally substitutedindole. In another embodiment, R⁵ is an optionally substituted6-membered aryl or heteroaryl ring. In some embodiments, R⁵ isoptionally substituted phenyl.

In some embodiments, J⁵ is H, halo, C₁₋₆ aliphatic, C₃₋₆cycloaliphatic,NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄aliphatic), COH, —CO(C₁₋₄ aliphatic), CONH₂, CONH(C₁₋₄ aliphatic),CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(haloC₁₋₄aliphatic), or halo(C₁₋₄ aliphatic).

For the avoidance of doubt, it should be understood that in a certainembodiment, p is 0, T¹ is O, R⁵ is optionally substituted phenyl, and R¹cyclopentyl or cyclohexyl.

In certain embodiments, the variables are defined as depicted incompounds I-1, I-2, I-3, and I-4.

One embodiment provides the following compounds:

General Synthetic Methodology

The compounds of this invention may be prepared in general by methodssuch as those depicted in the general schemes below, and the preparativeexamples that follow. Unless otherwise specified, Ring A, T¹, R¹, R⁴,R⁵, R^(A), and p are as defined herein.

Reagents and conditions: (i) NaH then CO(OMe)₂, toluene, (ii) TBABr₃,CH₂Cl₂, reflux, (iii) EtOH, reflux, (iv) NH₃ in MeOH, sealed tube, 90°C.

Scheme 1 above shows a general synthetic route that is used forpreparing the compounds 5-a (compounds of formula I wherein Ring A isthiazolyl and T¹, R¹, R⁴, R⁵, and p are as described herein). Compoundsof formula 5-a can be prepared from intermediate 1-a. The formation ofderivative 2-a is achieved by treating intermediate 1-a with acorresponding base and dimethyl carbonate. Bromination of 2-a usingTBABr₃ leads to a formation of 3-a, which can be reacted with acorresponding thioamide to give 4-a. This reaction is amenable to avariety of thioamides derivatives R²C(S)NH₂. The ester in 4-a can thenbe converted to an amide under suitable amide-formation conditions.

Reagents and conditions: (i) NaH, THF, reflux then EtOCOOEt, (ii)Dess-Martin periodinane, pyridine, DCM, (iii) R²CHO, NH₄OAc, AcOH, 65°C. (iv) NH₄OH, MeOH, 80° C.

Scheme 2 above shows a general synthetic route that is used forpreparing the compounds 5-b (compounds of formula I wherein Ring A isimidazolyl and T¹, R¹, R⁴, R⁵, and p are as described herein). Compoundsof formula 5-b can be prepared from intermediates 1-b. The formation ofderivatives 2-b is achieved by treating the intermediate 1-b with a baseand diethylcarbonate. Reaction of 2-b with Dess-Martin periodinanefollowed by cyclisation with an aldehyde R¹CHO gives intermediates 4-b.The reaction is amenable to a variety of aldehydes R¹CHO. Finally,derivatives 5-b were prepared according to step (iv) of Scheme 1.

Compound I-1 was prepared as shown in Scheme 2.

Reagents and conditions: (i) LDA, THF then MeCOO^(t)Bu, (ii) a)Bredereck's reagent, THF, reflux, b) H₂NNH₂.H₂O, EtOH, reflux, (iii)R²X, NaH, DMF, (iv) TFA, DCM, (v) COIm₂, DMF, then NH_(3gas).

Scheme 3 above shows a general synthetic route that is used forpreparing the compounds 6-c (compounds of formula I wherein Ring A ispyrazolyl and T¹, R¹, R⁴, R⁵, and p are as described herein). Compoundsof formula 6-c can be prepared from intermediates 1-c. The formation ofderivatives 2-c is achieved by treating the intermediate 1-c with a baseand tert-butylacetate. Reaction of 2-c with Bredereck's reagent followedby cyclisation with hydrazine gives intermediates 3-c, which can bealkylated with an alkylhalide R¹X to give compounds of formula 4-c. Thereaction is amenable to a variety of alkylhalides R¹X. Saponification oftert-butyl esters 4-c leads to compounds 5-c. Finally, derivatives 6-cwere prepared according to step (iv) of Scheme 1.

Accordingly, the present invention also provides processes for makingthe compounds of this invention.

One embodiment of this invention provides a process for preparing acompound of formula I:

wherein ring

-   and R¹, R⁴, T¹, R⁵, and p are defined herein;-   comprising-   reacting a compound of formula 4;

wherein Ring A, R¹, R⁴, T¹, R⁵, and p are defined herein and R^(A) is Hor C₁₋₆alkyl;

-   under suitable amide-formation conditions to form the compound of    formula I. Suitable amide formation conditions include, but are not    limited to, heating an ester with ammonia/MeOH, activating a    carboxylic acid with an activating agent, such as carbonyl    diimidazole, and then stirring the activated acid in the presence of    ammonia gas. In some embodiments, when Ring A is thiazolyl or    imidazolyl, R^(A) is C₁₋₆alkyl. When Ring A is pyrazolyl, R^(A) is    H.

Another embodiment comprises the step of reacting a compound of formula3-a:

wherein T¹, R⁴, R⁵, and p are defined herein;

-   with

wherein R¹ is as defined herein;

-   under suitable displacement and cyclization conditions to form a    compound of formula 4-a (a compound of formula 4    wherein ring

R^(A) is C₁₋₆alkyl; and R¹, R⁴, T¹, R⁵, and p are defined according toclaim 1):

Suitable displacement and cyclization conditions include heating thethioamide and the ketoester in a suitable solvent, such as, for example,ethanol.

Another embodiment comprises the step of reacting a compound of formula2-a:

wherein T¹, R⁴, R⁵, and p are defined herein; and R^(A) is C₁₋₆alkyl;

-   with a halogenating agent (e.g., tetrabutyl ammonium tribromide) to    form a compound of formula 3-a.

Another embodiment comprises the step of mixing a compound of formula1-a:

wherein T¹, R⁴, R⁵, and p are defined herein;

-   with dimethylcarbonate and a base in a suitable solvent to form a    compound of formula 2-a. Examples of bases include, but are not    limited to, NaH. Examples of suitable solvents include, but are not    limited to, toluene. In some embodiments, acetic acid is used to    quench the reaction.

Another embodiment comprises the steps of:

a) reacting a compound of formula 2-b;

wherein R⁴, T¹, R⁵, and p are defined herein; and R^(A) is C₁₋₆alkyl;

-   under suitable oxidizing conditions to form a compound of formula    3-b:

wherein R⁴, T¹, R⁵, and p are defined herein; and R^(A) is C₁₋₆alkyl;and

b) cyclizing the compound of formula 3-b with R¹CHO under suitablecyclization conditions to form a compound of formula 4-b (A compound offormula 4 wherein ring

R^(A) is C₁₋₆alkyl, and R¹, R⁴, T¹, R⁵, and p are defined according toclaim 1):

wherein R¹, R⁴, T¹, R⁵, and p are defined herein; and R^(A) isC₁₋₆alkyl.

Suitable cyclization conditions include, but are not limited to, NH₄OAcand AcOH at 65° C. Suitable oxidizing conditions include, but are notlimited to, treatment with Dess-Martin periodinane.

One embodiment comprises the step of reacting a compound of formula 1-b:

wherein R⁴, T¹, R⁵, and p are defined herein;

-   with a suitable base and diethylcarbonate under suitable conditions;    to form a compound of formula 2-b.

Another embodiment comprises the step of reacting a compound of formula4-c (A compound of formula 4 wherein ring

R^(A) is t-Butyl, and R¹, R⁴, T¹, R⁵, and p are defined according toclaim 1):

under suitable saponification conditions to form a compound of formula5-c:

wherein R¹, R⁴, T¹, R⁵, and p are defined herein. Suitablesaponification conditions include, but are not limited to, stirring thecompound in the presence of an acid (e.g., trifluoroacetic acid) and asolvent (e.g., CH₂Cl₂).

Yet another embodiment comprises the step of reacting a compound offormula 3-c:

wherein R⁴, T¹, R⁵, and p are defined herein;

-   with a suitable base (e.g., NaH) and an alkylhalide R¹X, wherein X    is a halo selected from F, Br, and I and R¹ is defined according to    claim 1; to form a compound of formula 4-c wherein R¹, R⁴, T¹, R⁵,    and p are defined herein.

Yet another embodiment comprises the steps of

a) reacting a compound of formula 2-c:

wherein R⁴, T¹, R⁵, and p are defined herein; with Bredereck's reagent;and

b) cyclizing the resulting compound with hydrazine to form a compound offormula 3-c; wherein R¹, R⁴, T¹, R⁵, and p are defined according toclaim 1.

One embodiment comprises the step of reacting a compound of formula 1-c:

wherein R⁴, T¹, R⁵, and p are defined herein;

-   with a suitable base (e.g., n-BuLi and diisopropyl ethylamine) and    tert-butylacetate under suitable conditions (e.g., stirring in    anhydrous THF at −78° C.) to form a compound of formula 2-c, wherein    R⁴, T¹, R⁵, and p are defined herein.    Utility as Protein Kinase Inhibitors

The present invention provides compounds and compositions that areuseful as inhibitors of protein kinases. In some embodiments, proteinkinases are Src-family kinases. In some embodiments, Lck.

As inhibitors of protein kinases, the compounds and compositions of thisinvention are particularly useful for treating or lessening the severityof a disease, condition, or disorder where a protein kinase isimplicated in the disease, condition, or disorder. In one aspect, thepresent invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease state. In another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where inhibition of enzymatic activityis implicated in the treatment of the disease. In another aspect, thisinvention provides a method for treating or lessening the severity of adisease, condition, or disorder with compounds that inhibit enzymaticactivity by binding to the protein kinase. Another aspect provides amethod for treating or lessening the severity of a kinase disease,condition, or disorder by inhibiting enzymatic activity of the kinasewith a protein kinase inhibitor.

In some embodiments, said protein kinase inhibitor is an Src-familykinase inhibitor. In some embodiment, said protein kinase inhibitor isan LCK kinase inhibitor.

As inhibitors of protein kinases, the compounds and compositions of thisinvention are also useful in biological samples. One aspect of theinvention relates to inhibiting protein kinase activity in a biologicalsample, which method comprises contacting said biological sample with acompound of formula I or a composition comprising said compound. Theterm “biological sample”, as used herein, means a sample that is not anin vivo sample, such as an in vitro or an ex vivo sample, including,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Another aspect of this invention relates to the study of protein kinasesin biological and pathological phenomena; the study of intracellularsignal transduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of the activated kinase. Alternate in vitro assays quantitatethe ability of the inhibitor to bind to the protein kinase and may bemeasured either by radiolabelling the inhibitor prior to binding,isolating the inhibitor/kinase complex and determining the amount ofradiolabel bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radioligands.

Another aspect of this invention provides compounds that are useful forthe treatment of diseases, disorders, and conditions including, but notlimited to, autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, cardiovascular diseases, hormone relateddiseases, allergies, asthma, and Alzheimer's disease.

For example, the present invention provides compounds that are usefulfor treating diseases of the respiratory tract including, withoutlimitation, reversible obstructive airways diseases including asthma,such as bronchial, allergic, intrinsic, extrinsic and dust asthma,particularly chronic or inveterate asthma (e.g. late asthma airwayshyper-responsiveness) and bronchitis. Additional diseases include,without limitation, those conditions characterised by inflammation ofthe nasal mucus membrane, including acute rhinitis, allergic, atrophicthinitis and chronic rhinitis including rhinitis caseosa, hypertrophicrhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa;membranous rhinitis including croupous, fibrinous and pseudomembranousrhinitis and scrofoulous rhinitis, seasonal rhinitis including rhinitisnervosa (hay fever) and vasomotor rhinitis, sarcoidosis, farmer's lungand related diseases, fibroid lung and idiopathic interstitialpneumonia.

Another aspect of this invention provides compounds that are useful fortreating diseases of the bone and joints including, without limitation,(pannus formation in) rheumatoid arthritis, seronegativespondyloarthropathis (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome,and systemic sclerosis.

Another aspect of this invention provides compounds that are useful fortreating diseases and disorders of other tissues and systemic disease,including, without limitation, multiple sclerosis, atherosclerosis,acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemiclupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,lepromatous leprosy, sezary syndrome and idiopathic thrombocytopeniapurpura, restenosis following angioplasty, tumours (for exampleleukemia, lymphomas), artherosclerosis, and systemic lupuserythematosus.

Another aspect of this invention provides compounds that are useful forallograft rejection, including, without limitation, acute and chronicallograft rejection following for example transplantation of kidney,heart, liver, lung, bone marrow, skin and cornea; and chronic graftversus host disease.

Another aspect of this invention provides a method for the treatment orlessening the severity of a disease selected from an autoimmune disease,an inflammatory disease, a proliferative or hyperproliferative disease,such as cancer, an immunologically-mediated disease, a bone disease, ametabolic disease, a neurological or neurodegenerative disease, acardiovascular disease, allergies, asthma, Alzheimer's disease, or ahormone related disease, comprising administering an effective amount ofa compound, or a pharmaceutically acceptable composition comprising acompound, to a subject in need thereof.

The term “cancer” includes, but is not limited to the following cancers:breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus;larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma;lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma; bone; colon, adenoma; pancreas, adenocarcinoma;thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; livercarcinoma and biliary passages; kidney carcinoma; myeloid disorders;lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx(oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum,large intestine, rectum; brain and central nervous system; and leukemia.

In certain embodiments, an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective inorder to treat said disease. The compounds and compositions, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of said disease.

In some embodiments, said disease is selected from a proliferativedisorder, a neurodegenerative disorder, an autoimmune disorder, andinflammatory disorder, and an immunologically-mediated disorder. In someembodiments, said disease is selected from hypercalcemia, restenosis,osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis,rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis,psoriasis, lupus, graft vs. host disease, T-cell mediatedhypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barresyndrome, chronic obtructive pulmonary disorder, contact dermatitis,cancer, Paget's disease, asthma, ischemic or reperfusion injury,allergic disease, atopic dermatitis, and allergic rhinitis. Diseasesthat are affected by Src activity, in particular, include hypercalcemia,osteoporosis, osteoarthritis, cancer, symptomatic treatment of bonemetastasis, and Paget's disease. In other embodiments, said disease isselected from hypercalcemia, osteoperosis, osteoarthritis, or sympomatictreatment of bone metastasis.

In yet other embodiments, said disease is a protein-kinase mediatedcondition. In some embodiments, said disease is an Src-mediated orLck-mediated disease.

The term “protein kinase-mediated condition”, as used herein, means anydisease or other deleterious condition in which a protein kinase plays arole. Such conditions include, without limitation, autoimmune diseases,inflammatory diseases, proliferative and hyperproliferative diseases,immunologically-mediated diseases, bone diseases, metabolic diseases,neurological and neurodegenerative diseases, cardiovascular diseases,hormone related diseases, allergies, asthma, and Alzheimer's disease.

The term “Src-mediated or Lck-mediated disease”, as used herein meansany disease or other deleterious condition in which Src or Lck is knownto play a role. Accordingly, these compounds are useful for treatingdiseases or conditions that are affected by the activity of one or moreSrc-family kinases. Such diseases or conditions include hypercalcemia,restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bonemetastasis, rheumatoid arthritis, inflammatory bowel disease, multiplesclerosis, psoriasis, lupus, graft vs. host disease, T-cell mediatedhypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barresyndrome, chronic obtructive pulmonary disorder, contact dermatitis,cancer, Paget's disease, asthma, ischemic or reperfusion injury,allergic disease, atopic dermatitis, and allergic rhinitis. Diseasesthat are affected by Src activity, in particular, include hypercalcemia,osteoporosis, osteoarthritis, cancer, symptomatic treatment of bonemetastasis, and Paget's disease. Diseases that are affected by Lckactivity, in particular, include autoimmune diseases, allergies,rheumatoid arthritis, and leukemia.

In another aspect of the present invention, pharmaceutically acceptablecompositions are provided, wherein these compositions comprise any ofthe compounds as described herein, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents.

As described herein, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The protein kinase inhibitors or pharmaceutical salts thereof may beformulated into pharmaceutical compositions for administration toanimals or humans. These pharmaceutical compositions, which comprise anamount of the protein inhibitor effective to treat or prevent a proteinkinase-mediated condition and a pharmaceutically acceptable carrier, areanother embodiment of the present invention. In some embodiments, saidprotein kinase-mediated condition is an Src-mediated or LCK-mediatedcondition.

The exact amount of compound required for treatment will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compounds of this invention can also exist as pharmaceuticallyacceptable derivatives.

A “pharmaceutically acceptable derivative” is an adduct or derivativewhich, upon administration to a patient in need, is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof. Examples of pharmaceuticallyacceptable derivatives include, but are not limited to, esters and saltsof such esters.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable ester, salt of an ester or other derivativeof a compound of this invention which, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favoured derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

According to another embodiment, the invention provides methods fortreating or preventing a protein kinase-mediated condition (in someembodiments, an Src or LCK-mediated condition) comprising the step ofadministering to a patient one of the above-described pharmaceuticalcompositions.

In some embodiments, said method is used to treat or prevent a conditionselected from hypercalcemia, osteoperosis, osteoarthritis, sympomatictreatment of bone metastasis, or any specific disease described above.

Another aspect of the invention relates to inhibiting protein kinaseactivity in a patient, which method comprises administering to thepatient a compound of formula I, or a composition comprising saidcompound.

Depending upon the particular protein kinase-mediated conditions to betreated or prevented, additional drugs, which are normally administeredto treat or prevent that condition, may be administered together withthe inhibitors of this invention. For example, chemotherapeutic agentsor other anti-proliferative agents may be combined with the proteinkinase inhibitors of this invention to treat proliferative diseases.

Those additional agents may be administered separately, as part of amultiple dosage regimen, from the protein kinase inhibitor-containingcompound or composition. Alternatively, those agents may be part of asingle dosage form, mixed together with the protein kinase inhibitor ina single composition.

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Those compounds may be analyzed byknown methods, including but not limited to LCMS (liquid chromatographymass spectrometry) and NMR (nuclear magnetic resonance). Compounds ofthis invention may be also tested according to these examples. It shouldbe understood that the specific conditions shown below are onlyexamples, and are not meant to limit the scope of the conditions thatcan be used for making, analyzing, or testing the compounds of thisinvention. Instead, this invention also includes conditions known tothose skilled in that art for making, analyzing, and testing thecompounds of this invention.

EXAMPLES

As used herein, the term “Rt(min)” refers to the HPLC retention time, inminutes, associated with the compound. Unless otherwise indicated, theHPLC method utilized to obtain the reported retention time is asfollows:

-   -   Column: ACE C8 column, 4.6×150 mm    -   Gradient: 0-100% acetonitrile+methanol 60:40 (20 mM Tris        phosphate)    -   Flow rate: 1.5 mL/minute    -   Detection: 225 nm.

Mass spec. samples are analyzed on a MicroMass Quattro Micro massspectrometer operated in single MS mode with electrospray ionization.Samples are introduced into the mass spectrometer using chromatography.

¹H-NMR spectra are recorded at 400 MHz using a Bruker DPX 400instrument. The following compounds of formula I were prepared andanalyzed as follows.

Intermediate 1

tert-Butyl 3-oxo-3-(4-phenoxyphenyl)propanoate

^(n)Butyllithium (2.5 M, 7.9 ml, 19.76 mmol) was added at −20° C. to asolution of di-iso-propylamine (3.29 ml, 23.24 mmol) in tetrahydrofuran(40 ml). The reaction mixture was stirred for 15 minutes under nitrogenat −20° C. then the mixture was allowed to cool down to −78° C.tert-Butylacetate (2.64 ml, 19.67 mmol) was added and the mixture wasstirred at −78° C. for 20 minutes. A solution of ethyl 4-phenoxybenzoate(2.17 g, 8.94 mmol) in tetrahydrofuran (5 ml) was further added to thisand the resulting mixture was stirred at −78° C. for 50 minutes. Asaturated solution of NH₄Cl was added and the whole was extracted withEtOAc. The organics were dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by silica gel chromatography elutingwith 8% Et₂O in petroleum ether to afford the title compound as acolourless oil (1.53 g, 55% yield). MS (ES+) m/e=313. ¹H NMR (CDCl₃) δH1.47 (9H, s), 3.88 (2H, s), 7.02 (2H, d), 7.10 (2H, d), 7.24 (1H, t),7.43 (2H, t), 7.94 (2H, d).

Intermediate 2

tert-Butyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate

To tert-Butyl 3-oxo-3-(4-phenoxyphenyl)propanoate (559 mg, 1.80 mmol) intetrahydrofuran, was added Bredereck's reagent (1.18 mL, 5.70 mmol). Thereaction mixture was stirred for 6 hours under nitrogen at reflux. Thereaction mixture was concentrated in vacuo and taken up in EtOH (5 mL).Hydrazine monohydrate (79 μL, 1.63 mmol) was added and the reactionmixture was heated at reflux for 16 hours. The crude mixture wasconcentrated in vacuo, taken up in EtOAc, washed with water, a saturatedaqueous solution of NaHCO₃ and brine. The organic phase was dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (eluting with 40% EtOAc in petroleum ether) toafford the title compound (264 mg, 48% yield). MS (ES+) m/e=337. ¹H NMR(CDCl₃) δH 1.52 (9H, s), 7.04 (2H, d), 7.06 (2H, d), 7.16 (1H, t), 7.38(2H, t), 7.66 (2H, d), 7.95 (1H, s), 10.90 (1H, br s).

Intermediate 3

tert-Butyl 1-cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate

To tert-Butyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (156 mg,0.46 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride, 60%in mineral oil (20.8 μg, 0.52 mmol). After the gas evolution ceased(about 5 minutes), cyclopentyl iodide (59 μL, 0.51 mmol) was addeddropwise and the mixture was stirred for 16 hours at room temperature.EtOAc was added and the crude mixture was washed with a saturatedaqueous solution of NaHCO₃. The aqueous phase was further extracted withEtOAc (3 times). The combined organic extracts were washed with waterand brine. The organics were dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by silica gel chromatography (elutingwith petroleum ether/DCM) to afford the title compound as a white solid(0.131 g, 69% yield). MS (ES+) m/e=405. ¹H NMR (CDCl₃) δH 1.51 (9H, s),1.70-1.80 (2H, m), 1.85-2.00 (2H, m), 2.02-2.13 (2H, m), 2.18-2.30 (2H,m), 4.71 (1H, quint.), 7.06 (4H, d), 7.12 (1H, t), 7.35 (2H, t), 7.76(2H, d), 7.95 (1H, s).

Example 1

1-Cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide I-2

Trifluoroacetic acid (5 mL) was added to a solution of tert-Butyl1-cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (129 mg,0.32 mmol) in dichloromethane (5 mL). The reaction mixture was stirredat room temperature for 16 hours. The mixture was concentrated in vacuoand coevaporated 3 times with DCM.

The residue was dissolved in N,N-dimethylformamide (2 mL) and carbonyldiimidazole (88 mg, 0.54 mmol) was added. The reaction mixture wasstirred at room temperature for 3 hours then, cooled down to 0° C. withan ice bath. Ammonia gas was bubbled into the solution for a few minutesand the mixture was stirred at room temperature for 40 minutes. Waterwas added and the white solid was filtered, rinsed with more water anddried. The residue was purified by reverse phase preparative HPLC[Waters Delta-Pak C18, 15 uM, 100 A column, gradient 10%-100% B (solventA: 0.05% TFA in water; solvent B: CH₃CN) over 10 minutes at 25 mL/min]to afford the title compound as a white solid (88 mg, 79%) as a whitesolid. MS (ES+) m/e=348. ¹H NMR (CDCl₃) δH 1.70-2.00 (4H, m), 2.00-2.12(2H, m), 2.17-2.9 (2H, m), 4.71 (1H, quint.), 5.63 (2H, br s), 7.05-7.14(4H, m), 7.18 (1H, t), 7.39 (2H, t), 7.60 (2H, d), 8.08 (1H, s).

Intermediate 4

Methyl 3-oxo-3-(4-phenoxyphenyl)propanoate

In a three-necked flask equipped with a reflux condenser and stirbarunder nitrogen was added 4′-phenoxyacetophenone (10 g, 47.1 mmol) intoluene (40 mL) dropwise at reflux to a suspension of sodium hydride(60% dispersion in mineral oil; 4.71 g, 0.12 mmol) in dimethylcarbonate(10.6 g, 0.12 mol) and toluene (20 mL). Ageing the reaction for 30 minsled to a solid mass to which was added acetic acid (5 mL) in water (25mL). Added EtOAc (30 mL) and the organics were dried (MgSO₄), filteredand concentrated in vacuo. The residue was passed through a silica padeluting with EtOAc/petroleum ether (3/20) and then concentrated.Petroleum ether was added and the less dense layer was decanted to givethe ketoester (11.7 g, 92%) as a yellow oil, which solidified onstanding. MS (ES+) m/e=271. ¹H NMR: (CDCl₃) 3.87 (3H, s), 3.99 (2H, s),7.02 (2H, d), 7.08 (2H, d), 7.25 (1H, t), 7.45 (2H, t), 7.94 (2H, d).

Intermediate 5

Cyclopentanecarbothioamide

Ammonia was bubbled through a solution of cyclopentanecarbonyl chloride(5.46 g, 41.1 mmol) in THF (60 mL) for 30 seconds. After 10 min, theammonium chloride produced was filtered off and the filtrateconcentrated. Then added EtOAc and water and separated the layers andre-extracted with a further portion of EtOAc. The combined organics weredried (MgSO₄), filtered and concentrated in vacuo to give the amide(4.46 g, 96%) as a clear oil. The amide (2.60 g, 23.0 mmol) from abovewas dissolved in THF (60 mL) and Lawesson's reagent (4.52 g, 11.18 mmol)was added under nitrogen. The mixture was heated at 70° C. After 90 min,toluene was added (30 mL) and heating continued overnight. Then thereaction mixture was concentrated and partitioned between EtOAc andwater. The organic layer was concentrated and the residue purified bycolumn chromatography (eluting with EtOAc/Pet ether, 1/1) to give thethioamide (2.44 g, 82%). ¹H NMR: (DMSO) 1.45-1.88 (8H, m), 2.90 (1H,quin), 9.13 (1H, br s), 9.32 (1H, br s).

Intermediate 6

Methyl 2-cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxylate

To the ketoester (652 mg, 2.41 mmol) was added tetrabutyl ammoniumtribromide (1.22 g, 2.53 mmol) at 0° C. in CH₂Cl₂ (20 mL). After 5 minthe ice-bath was removed and the reaction was heated to reflux. After 3h, the reaction was washed with sat. aq. NaHCO₃ and then concentrated.To this residue was added cyclopentanecarbothioamide (276 mg, 2.14 mmol)in ethanol (12 mL) and heated to 60° C. for 30 min. Concentrated thereaction and purified directly by column chromatography (eluting withEtOAc/Pet ether, 1/3) to give the thiazole (360 mg, 44%). MS (ES+)m/e=380. ¹H NMR: (CDCl₃) 1.70-1.95 (6H, m), 2.20-2.29 (2H, m), 3.45-3.55(1H, m), 7.05-7.09 (4H, m), 7.17 (1H, t), 7.39 (2H, t), 7.78 (2H, d).

Example 2

2-Cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxamide I-3

Methyl 2-cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxylate (265 mg,0.70 mmol) was suspended in methanolic ammonia (7M, 10 mL) in a sealedvessel, which was then heated to 90° C. in an oil bath overnight. Thereaction was then concentrated and purified by column chromatography(eluting with EtOAc/PE, 1/1) to give the aminothiazole (56 mg, 22%) as awhite solid. MS (ES+) m/e=365. ¹H NMR: (DMSO) 1.62-1.71 (2H, m),1.72-1.85 (4H, m), 2.08-2.20 (2H, m), 3.46 (1H, quin), 7.02-7.10 (4H,m), 7.18 (1H, t), 7.42 (2H, t), 7.60-7.78 (4H, m).

Compound I-4 was prepared similarly to compound I-3 except substitutinga cyclohexyl group for the cyclopentyl group.

Analytical Data

LCMS HPLC Cmpd M+ NMR_RESULT Rt/Min I-1 348.30 ¹H (DMSO) 1.61-1.72 (2H,m), 9.20 1.74-1.89 (4H, m), 2.03-2.12 (2H, m), 3.24 (1H, quintet),7.07-7.11 (4H, m), 7.20 (1H, t), 7.32 (1H, bs), 7.41-7.47 (3H, m), 7.77(2H, d). I-2 348.30 ¹H (CDC13) 1.70-2.00 (4H, m), 9.612 2.00-2.12 (2H,m), 2.17-2.9 (2H, m), 4.71 (1H, quint.), 5.63 (2H, br s), 7.05-7.14 (4H,m), 7.18 (1H, t), 7.39 (2H, t), 7.60 (2H, d), 8.08 (1H, s) I-3 365.23 ¹H(DMSO) 1.62-1.71 (2H, m), 9.75 1.72-1.85 (4H, m), 2.08-2.20 (2H, m),3.46 (1H, quin), 7.02-7.10 (4H, m), 7.18 (1H, t), 7.42 (2H, t),7.60-7.78 (4H, m). I-4 379.00 ¹H (DMSO) 1.11-1.59 95H, m), 10.391.63-1.86 (3H, m), 2.04-2.13 (2H, m), 2.96-3.06 (1H, m), 7.01-7.10 (4H,m), 7.15-7.21 (1H, m), 7.38-7.48 (2H, m), 7.58-7.79 (4H, m).

Example 3

The compounds are evaluated as inhibitors of human Src kinase using aspectrophotometric assay.

Src Inhibition Assay

An assay buffer solution was prepared which consisted of 25 mM HEPES (pH7.5), 10 mM MgCl₂, 250 μM NADH, 3 mM phosphoenolpyruvate, 60 μg/mLpyruvate kinase, 21 μg/mL lactate dehydrogenase, 113 μM ATP and 28 nMSrc. To 60 μL of this solution, in a 96 well plate, was added 2 μL oftest compound stock solution in DMSO and the mixture allowed toequilibrate for 10 mins at 30° C. The enzyme reaction was initiated bythe addition of 5 μL 10 mg/mL poly Glu, Tyr (4:1) prepared in 25 mMHEPES (pH 7.5). Final assay concentrations of Src and ATP were 25 nM and100 μM respectively. Initial rate data was determined from the rate ofchange of absorbance at 340 nM (corresponding to stoichiometricconsumption of NADH) using a Molecular Devices Spectramax plate reader(Sunnyvale, Calif.) over 10 mins at 30° C. For each Ki determination 8data points covering the test compound concentration range of 0-7.5 μMwere obtained in duplicate. K_(i) values were calculated from initialrate data by non-linear regression using the Prism software package(Prism 4.0a, Graphpad Software, San Diego, Calif.).

Compound I-1 was found to inhibit Src at a K_(i) value of 100 nM-500 nM.Compounds I-2, I-3, and I-4 were found to inhibit Src at a K_(i) valueof >1 μM.

Example 4

The compounds are evaluated as inhibitors of human Lck kinase using aspectrophotometric assay.

Lck Inhibition Assay

An assay buffer solution was prepared which consisted of 25 mM HEPES (pH7.5), 10 mM MgCl₂, 250 μM NADH, 3 mM phosphoenolpyruvate, 43 μg/mLpyruvate kinase, 14 μg/mL lactate dehydrogenase, 560 μM ATP and 67 nMLck. To 60 μL of this solution, in a 96 well plate, was added 2 μL oftest compound stock solution in DMSO and the mixture allowed toequilibrate for 10 minutes at 30° C. The enzyme reaction was initiatedby the addition of 5 μL 15 mg/mL poly Glu, Tyr (4:1) prepared in 25 mMHEPES (pH 7.5). Final assay concentrations of Lck and ATP are 60 nM and500 μM respectively. Initial rate data was determined from the rate ofchange of absorbance at 340 nM (corresponding to stoichiometricconsumption of NADH) using a Molecular Devices Spectramax plate reader(Sunnyvale, Calif.) over 10 min at 30° C. For each Ki determination 8data points covering the test compound concentration range of 0-7.5 μMare obtained in duplicate. Ki values are calculated from initial ratedata by non-linear regression using the Prism software package (Prism4.0a, Graphpad Software, San Diego, Calif.).

Compounds of this invention were found to inhibit Lck at a K_(i) valueof <1 μM. More specifically, compound I-1 was found to inhibit Lck at aK_(i) value of <100 nM. Compound I-2 and compound I-3 were found toinhibit Lck at a K_(i) value of 100 nM-500 nM. Compound I-4 is expectedto inhibit Lck at a K_(i) value of <1 μM (based on assay results in viewof the relatively low solubility of 1-4 under the assay conditions).

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize or encompass the compounds, methods, andprocesses of this invention. Therefore, it will be appreciated that thescope of this invention is to be defined by the appended claims.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein R¹ is a 3-7membered monocyclic cycloalkyl optionally substituted with 0-4 J¹; Ring

R⁴ is H, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, halo(C₁₋₄ aliphatic), 3-8membered heterocyclyl, halo, NO₂, CN, OH, OR″, SH, SR″, NH₂, NHR″, NR″₂,COH, COR″, CO₂H, CO₂R″, CONH₂, CONHR″, CONR″₂, OC(O)R″, OC(O)NH₂,OC(O)N(H)R″, OC(O)NR″₂, N(H)C(O)R″, N(R″)C(O)R″, N(H)CO₂R″, N(R″)CO₂R″,N(H)CO₂H, N(R″)CO₂H, N(H)CONH₂, N(H)C(O)N(H)R″, N(H)CONR″₂, SO₂NH₂,SO₂N(H)R″, SO₂NR″₂, N(H)SO₂R″, N(R″)SO₂R″, P(O)R′, PO₂R′, P(O)R′₂, orP(O)(OR′)₂; R″ is unsubstituted C₁₋₆aliphatic or C₁₋₄ haloaliphatic; ortwo R″ groups, together with the atom to which they are bound, form anunsubstituted 3-8 membered nonaromatic monocyclic ring having 0-1heteroatoms independently selected from O, N, and S; T¹ is a C₁₋₆aliphatic chain wherein 0-3 methylene units of the chain are optionallyreplaced with —N(R)—, —O—, —S—,—C(O)—, —C(═NR)—, —C(═NOR)—, —SO—, or—SO₂—; each T¹ is optionally substituted with 0-2 J^(T); R⁵ is a 5-10membered aromatic ring containing 0-4 heteroatoms selected from O, N,and S; each R⁵ is optionally substituted with 0-5 J⁵; J⁵ is H, C₁₋₆aliphatic, C₃₋₈cycloaliphatic, halo(C₁₋₄ aliphatic), 3-8 memberedheterocyclyl, halo, NO₂, CN, OH, OR', SH, SR′, NH₂, N(H)R′, NR′₂, C(O)H,C(O)R′, CO₂H, CO₂R′, C(O)NH₂, C(O)N(H)R′, C(O)NR′₂, OC(O)R′, OC(O)NH₂,OC(O)NHR′, OC(O)N(R′)₂, N(H)C(O)R′, N(R′)C(O)R′, N(H)CO₂R′, N(R′)CO₂R′,N(H)CO₂H, N(R′)CO₂H, N(H)CONH₂, N(H)C(O)NHR′, N(H)CON(R′)₂, SO₂NH₂,SO₂NHR′, SO₂NR′₂, N(H)SO₂R′, N(R′)SO₂R′, P(O)R′, PO₂R′, P(O)R′₂, orP(O)OR′₂; R is H or unsubstituted C₁₋₆aliphatic; R′ is unsubstitutedC₁₋₆aliphatic or C₁₋₄ haloaliphatic; or two R′ groups, together with theatom to which they are bound, form an unsubstituted 3-8 memberednonaromatic monocyclic ring having 0-1 heteroatoms independentlyselected from O, N, and S; J¹ is M¹ or -Y¹-M¹; each Y¹ is independentlyan unsubstituted C₁₋₆aliphatic optionally replaced with 0-3 occurrencesof —N(R)—, —O—, —S—, —C(O)—, —SO—, or —SO₂—; each M¹ is independently H,C₁₋₆ aliphatic, C₃₋₈cycloaliphatic, halo(C₁₋₄ aliphatic), —O(haloC₁₋₄aliphatic), 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl,halo, NO₂, CN, OH, OR′, SH, SR′, NH₂, N(H)R′, NR′₂, C(O)H, C(O)R′, CO₂H,CO₂R′, C(O)NH₂, C(O)NHR′, C(O)NR′₂, OC(O)R′, OC(O)NH₂, OC(O)NHR′,OC(O)N(R′)₂, N(H)C(O)R′, N(R′)C(O)R′, N(H)CO₂R′, N(R′)CO₂R′, N(H)CO₂H,N(R′)CO₂H, N(H)C(O)NH₂, N(H)C(O)N(H)R′, N(H)C(O)NR′₂, SO₂NH₂, SO₂NHR′,SO₂N(R′)₂, NHSO₂R′, NR′SO₂R′, P(O)R′, PO₂R′, P(O)R′₂, or P(OOR′₂; eachR⁴, J⁵, and M¹ is independently and optionally substituted with 0-5 J;each J^(T) and J is independently H, halo, C₁₋₆ aliphatic,C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —CO(C₁₋₄ aliphatic), CONH₂,CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄ aliphatic),—O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic); p is 0-4.
 2. Thecompound according to claim 1, wherein T¹-R⁵ is bonded in the paraposition (relative to bond c) as shown in formula II:


3. The compound according to claim 2, wherein R¹ is a 5 or 6 memberedcycloalkyl ring.
 4. The compound according to claim 3, wherein Ring A is


5. The compound according to claim 4, wherein R⁴ is H, halo, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic),COH, —CO(C₁₋₄ aliphatic),CONH₂, CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).
 6. Thecompound according to claim 5, wherein T¹ is O, N, S, —C(O)N(R)— or—N(R)C(O)—.
 7. The compound according to claim 6, wherein T¹ is O. 8.The compound according to claim 6, wherein R is H.
 9. The compoundaccording to claim 6, wherein R⁵ is an optionally substituted indole.10. The compound according to claim 6, wherein R⁵ is an optionallysubstituted 6-membered aryl or heteroaryl ring.
 11. The compoundaccording to claim 10, wherein R⁵ is optionally substituted phenyl. 12.The compound according to claim 11, wherein J⁵ is H, halo, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —CO(C₁₋₄ aliphatic),CONH₂, CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).
 13. Thecompound according to claim 3, wherein Ring A is


14. The compound according to claim 13, wherein R⁴ is H, halo, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —CO(C₁₋₄ aliphatic),CONH₂, CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).
 15. Thecompound according to claim 14, wherein T¹ is O, N, S, —C(O)N(R)— or—N(R)C(O)—.
 16. The compound according to claim 15, wherein T¹ is O. 17.The compound according to claim 15, wherein R is H.
 18. The compoundaccording to claim 15, wherein R⁵ is an optionally substituted indole.19. The compound according to claim 15, wherein R⁵ is an optionallysubstituted 6-membered aryl or heteroaryl ring.
 20. The compoundaccording to claim 19, wherein R⁵ is optionally substituted phenyl. 21.The compound according to claim 20, wherein J⁵ is H, halo, C₁₋₆aliphatic, C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —CO(C₁₋₄ aliphatic),CONH₂, CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).
 22. Thecompound according to claim 1, wherein the compound has one or more ofthe following variable definitions: a) Ring

b) T¹ is O; c) R⁵ is optionally substituted phenyl; d) R⁴ is H, halo,C₁₋₆ aliphatic, C₃₋₆cycloaliphatic, NO₂, CN, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), COH, —CO(C₁₋₄ aliphatic),CONH₂, CONH(C₁₋₄ aliphatic), CON(C₁₋₄ aliphatic)₂, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(haloC₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).
 23. Thecompound according to claim 1, wherein: T¹ is O; p is 0; R⁵ isoptionally substituted phenyl; R¹ is cyclopentyl or cyclohexyl.
 24. Thecompound according to claim 1 selected from the following:


25. A composition comprising a compound according to any one of claims1-24, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.26. A method of inhibiting protein kinase activity in a biologicalsample comprising contacting said biological sample with a compoundaccording to claim 1, wherein said protein kinase is Lck.
 27. Acomposition for coating an implantable device comprising a compoundaccording to claim 1 and a carrier suitable for coating said implantabledevice.
 28. A process for preparing a compound of formula I:

wherein ring

and R¹, R⁴, T¹, R⁵, and p are defined according to claim 1; comprisingreacting a compound of formula 4;

wherein Ring A, R¹, R⁴, T¹, R⁵, and p are defined according to claim 1and R^(A) is H or C₁₋₆alkyl; under suitable amide-formation conditionsto form the compound of formula I.
 29. The process of claim 28, furthercomprising the step of reacting a compound of formula 3-a:

wherein R^(A) is C₁₋₆alkyl; with

under suitable displacement and cyclization conditions to form thecompound of formula 4 wherein ring

 and R^(A) is H or C₁₋₆alkyl.
 30. The process of claim 29, furthercomprising the step of reacting a compound of formula 2-a:

wherein R^(A) is C₁₋₆alkyl; with a halogenating agent to form a compoundof formula 3-a.
 31. The process of claim 30, further comprising the stepof mixing a compound of formula 1-a:

with dimethylcarbonate and a base in a suitable solvent to form acompound of formula 2-a.
 32. The process of claim 28, further comprisingthe steps of: (a) reacting a compound of formula 2-b;

wherein R^(A) is C₁₋₆alkyl; under suitable oxidizing conditions to forma compound of formula 3-b:

wherein R^(A) is C₁₋₆alkyl; (b) cyclizing the compound of formula 3-bwith R¹CHO under suitable cyclization conditions to form a compound offormula 4, wherein ring

 and R^(A) is C₁₋₆alkyl.
 33. The process of claim 32, further comprisingthe step of reacting a compound of formula 1-b:

with a suitable base and diethylcarbonate under suitable conditions; toform a compound of formula 2-b:

wherein R^(A) is C₁₋₆alkyl.
 34. The process of claim 28, furthercomprising the step of reacting a compound of formula 4, wherein ring

 and R^(A) is t-butyl; under suitable saponification conditions to forma compound of formula 5-c:


35. The process of claim 34, further comprising the step of reacting acompound of formula 3-c:

with a suitable base and an alkylhalide R¹X, wherein X is a haloselected from F, Br, and I; to form a compound of formula 4 wherein ring

 and R^(A) is t-butyl.
 36. The process of claim 35, further comprisingthe steps of (a) reacting a compound of formula 2-c:

with Bredereck's reagent; and then (b) cyclizing the resulting compoundwith hydrazine to form a compound of formula 3-c.
 37. The process ofclaim 36, further comprising the step of reacting a compound of formula1-c:

with a suitable base and tert-butylacetate under suitable conditions toform a compound of formula 2-c: